This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by de Muys, J.-M.
Right arrow Articles by Rando, R. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by de Muys, J.-M.
Right arrow Articles by Rando, R. F.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 1999, p. 1835-1844, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2'-Deoxy-3'-Oxa-4'-Thiocytidine

Jean-Marc de Muys,1 Henriette Gourdeau,1 Nghe Nguyen-Ba,1 Debra L. Taylor,2 Parvin S. Ahmed,2 Tarek Mansour,1,dagger Celine Locas,1 Nathalie Richard,3 Mark A. Wainberg,3 and Robert F. Rando1,*

MRC Collaborative Centre Mill Hill, London, England,2 and McGill University AIDS Centre, Jewish General Hospital, Montreal,3 BioChem Pharma, Inc., Laval,1 Quebec, Canada

Received 20 January 1999/Returned for modification 26 April 1999/Accepted 13 May 1999

The racemic nucleoside analogue 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5'-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The Ki values for dOTC-TP obtained against human DNA polymerases alpha , beta , and gamma  were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 µM, rising to only 2.53 and 2.5 µM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [3H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 µM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 µM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.

* Corresponding author. Mailing address: BioChem Pharma, Inc., 275 Armand-Frappier Blvd., Laval, Quebec H7V 4A7, Canada. Phone: 450-978-7873. Fax: 450-978-7946. E-mail: randor{at}biochempharma.com.

dagger Present address: Wyeth Ayerst Research, Pearl River, NY 10965.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1835-1844, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Oliveira, M., Moisi, D., Spira, B., Cox, S., Brenner, B. G., Wainberg, M. A. (2009). Apricitabine Does Not Select Additional Drug Resistance Mutations in Tissue Culture in Human Immunodeficiency Virus Type 1 Variants Containing K65R, M184V, or M184V plus Thymidine Analogue Mutations. Antimicrob. Agents Chemother. 53: 1683-1685 [Abstract] [Full Text]  
  • Ntemgwa, M., Wainberg, M. A., Oliveira, M., Moisi, D., Lalonde, R., Micheli, V., Brenner, B. G. (2007). Variations in Reverse Transcriptase and RNase H Domain Mutations in Human Immunodeficiency Virus Type 1 Clinical Isolates Are Associated with Divergent Phenotypic Resistance to Zidovudine. Antimicrob. Agents Chemother. 51: 3861-3869 [Abstract] [Full Text]  
  • Holdich, T., Shiveley, L. A., Sawyer, J. (2007). Effect of Lamivudine on the Plasma and Intracellular Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers. Antimicrob. Agents Chemother. 51: 2943-2947 [Abstract] [Full Text]  
  • Bethell, R., De Muys, J., Lippens, J., Richard, A., Hamelin, B., Ren, C., Collins, P. (2007). In Vitro Interactions between Apricitabine and Other Deoxycytidine Analogues. Antimicrob. Agents Chemother. 51: 2948-2953 [Abstract] [Full Text]  
  • Rando, R. F., Obara, S., Osterling, M. C., Mankowski, M., Miller, S. R., Ferguson, M. L., Krebs, F. C., Wigdahl, B., Labib, M., Kokubo, H. (2006). Critical design features of phenyl carboxylate-containing polymer microbicides.. Antimicrob. Agents Chemother. 50: 3081-3089 [Abstract] [Full Text]  
  • Gu, Z., Allard, B., de Muys, J. M., Lippens, J., Rando, R. F., Nguyen-Ba, N., Ren, C., McKenna, P., Taylor, D. L., Bethell, R. C. (2006). In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection. Antimicrob. Agents Chemother. 50: 625-631 [Abstract] [Full Text]  
  • Smith, P. F., Forrest, A., Ballow, C. H., Martin, D. E., Proulx, L. (2000). Safety, Tolerability, and Pharmacokinetics of Single Oral Doses of BCH-10652 in Healthy Adult Males. Antimicrob. Agents Chemother. 44: 2816-2823 [Abstract] [Full Text]  
  • Smith, P. F., Forrest, A., Ballow, C. H., Martin, D. E., Proulx, L. (2000). Absolute Bioavailability and Disposition of (-) and (+) 2'-Deoxy- 3'-Oxa-4'-Thiocytidine (dOTC) following Single Intravenous and Oral Doses of Racemic dOTC in Humans. Antimicrob. Agents Chemother. 44: 1609-1615 [Abstract] [Full Text]  
  • Stoddart, C. A., Moreno, M. E., Linquist-Stepps, V. D., Bare, C., Bogan, M. R., Gobbi, A., Buckheit, R. W. Jr., Bedard, J., Rando, R. F., McCune, J. M. (2000). Antiviral Activity of 2'-Deoxy-3'-Oxa-4'-Thiocytidine (BCH-10652) against Lamivudine-Resistant Human Immunodeficiency Virus Type 1 in SCID-hu Thy/Liv Mice. Antimicrob. Agents Chemother. 44: 783-786 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»